Compounds with dihydropyridazinone and pyridazinone groups substituted at 3-position of pyrazolopyridine ring have been disclosed in Japanese Unexamined Patent publication Nos. Hei 2-243689 and Hei 4-253978. However, with the compounds claimed in these unexamined patent publications, substituents at 2-position of pyrazolopyridine ring are limited to aryl groups such as benzene derivatives, including no inventive compounds wherein they are alkyl groups. Also, pyrazolopyridine derivatives with bronchodilating effect are disclosed in Japanese Unexamined Patent Publication No. Hei 8-12673, but compounds disclosed therein have quite different structure from that of the inventive compounds.
Since it was discovered that the bronchodilating effect is caused through enhanced cyclic AMP and GMP in cells, enzymes that decompose cyclic AMP and GMP and inhibiting drugs of phosphodiesterase are attracting an attention as bronchodilator. While theophylline is mentioned for a common drug as an inhibiting drug of phosphodiesterase, theophylline has low selectivity to target organ. For this reason, when using theophylline to asthmatic patients for the purpose of bronchodilating effect, undesirable effects such as increased heart rate, vomition and central action occur very frequently as well. Developing a drug that acts selectively to respiratory tract being a target organ and expresses the bronchodilating effect via potent phosphodiesterase-inhibiting activity is being desired strongly as an ideal drug with low side effect.
As a result of diligent studies an a compound with phosphodiesterase-inhibiting activity and with selective-to-respiratory tract and potent bronchodilating effect, the inventors have found that novel pyrazolopyridinepyridazinone derivatives with different structure from that of bronchodilators known so far have high safety, too, and have selective-to-respiratory tract and potent bronchodilating effect, leading to the completion of the invention.
Namely, the invention provides pyrazolopyridinepyridazinone derivatives characterized by being represented by a general formula (1) ##STR1##
[wherein R.sup.1 denotes a lower alkyl group with carbon atoms of 1 to 4 or cycloalkyl group with carbon atoms of 3 to 6, and R.sup.2, R.sup.3, R.sup.4 and R.sup.5 denote identically or differently hydrogen atoms, lower alkyl groups with carbon atoms of 1 to 4 or phenyl groups, or R.sup.3 and R.sup.5 may combine to form a double bond], pharmacologically acceptable salts, and bronchodilator having at least one or more kinds of them as effective ingredients.
For the pharmacologically acceptable salts of the compounds represented by the general formula (1) in the invention, acid adducts like hydrochloride, hydrobromide, citrate, methanesulfonate and tartrate are mentioned.
Moreover, in the general formula (1) of the invention, "lower alkyl group" indicates straight chain or branched hydrocarbons with carbon atoms of 1 to 4 such as methyl, ethyl and propyl and, for "cycloalkyl group", cyclic hydrocarbons with carbon atoms of 3 to 6 are mentioned. Moreover, for "halogen atom", chlorine, bromine and iodine atoms are mentioned.
According to the invention, compounds with R.sup.3 and R.sup.5 not forming a double bond among compounds represented by the general formula (1) aforementioned, i.e. compounds represented by a general formula (1a) ##STR2##
[wherein R.sup.1 is as described above, and R.sup.2, R.sup.4, R.sup.6 and R.sup.8 denote identically or differently hydrogen atoms, lower alkyl groups with carbon atoms of 1 to 4 or phenyl groups], can be prepared by reacting compounds represented by a following general formula (6) with hydrazine. ##STR3##
[wherein R.sup.1, R.sup.2, R.sup.4, R.sup.6 and R.sup.8 are as described above].
The reaction can be conducted at room temperature to solvent-refluxing temperature as a reaction temperature in an organic solvent, for example, benzene, toluene, acetic acid, ethanol or the like. At this time, ethanol is preferable as a reaction solvent and the reaction temperature is preferable to be refluxing temperature under heat.
Moreover, compounds with R.sup.3 and R.sup.5 combined to form a double bond in the general formula (1), i.e. compounds represented by a general formula (1c) ##STR4##
[wherein R.sup.1, R.sup.2 and R.sup.4 are as described above], can be prepared by oxidizing compounds represented by a general formula (1b) ##STR5##
[wherein R.sup.1, R.sup.2 and R.sup.4 are as described above].
It is preferable to conduct the reaction by reacting with bromine in a solvent of acetic acid, and the reaction temperature is preferable to be 50 to 60.degree. C.
The compounds represented by the general formula (6) aforementioned can be prepared through following three routes. ##STR6## ##STR7##
In the synthetic route 1, compounds represented by a general formula (5) ##STR8##
[wherein R.sup.1, R.sup.2, R.sup.4, R.sup.6 and R.sup.8 are as described above, and R.sup.7 denotes a lower alkyl group with carbon atoms of 1 to 3], can be prepared by reacting compounds represented by a general formula (2) with compounds represented by a general formula (4) ##STR9##
[wherein R.sup.1, R.sup.2 and R.sup.6 are as described above]. ##STR10##
[wherein X denotes a halogen atom, and R.sup.4, R.sup.7 and R.sup.8 are as describe above].
It is preferable to conduct the reaction at 0.degree. C. to solvent-refluxing temperature, though the reaction temperature is not restricted particularly, in the presence of inorganic base such as potassium t-butoxide or potassium hydride, preferably sodium hydride, using tetrahydrofuran, 1,4-dioxane, or 1,2-dimethoxyethane, preferably dimethylformamide.
In the synthetic route 1, the compounds of general formula (6) ##STR11##
[wherein R.sup.1, R.sup.2, R.sup.4, R.sup.6 and R.sup.8 are as described above], can be prepared by hydrolyzing the compounds represented by the general formula (5) aforementioned.
In the case of acid catalyst, it is preferable to conduct the hydrolysis by heating to 80 to 120.degree. C., using hydrochloric acid or hydrobromic acid. Moreover, in the case of alkali catalyst, it is preferable to conduct at room temperature in an alcoholic solvent such as methanol or ethanol or in a solvent such as tetrahydrofuran or dimethylformamide, using aqueous solution of sodium hydroxide or aqueous solution of potassium hydroxide.
In the synthetic route 2, compounds represented by a general formula (16) ##STR12##
[wherein R.sup.1 and R.sup.2 are as described above, and R denotes a lower alkyl group with carbon atoms of 1 to 3], can be prepared by reacting compounds represented by a following general formula (2a) with compounds represented by a general formula (3) ##STR13##
[wherein R.sup.1 and R.sup.2 are as described above]. EQU CO(OR).sub.2 (3)
[wherein R is as described above].
It is preferable to conduct the reaction by refluxing under heat as a reaction temperature in the presence of inorganic base such as potassium t-butoxide or potassium hydride, preferably sodium hydride, using solvent amount of the compounds of general formula (3).
In the synthetic route 2, compounds represented by a general formula (17) ##STR14##
[wherein R, R.sup.1, R.sup.2, R.sup.4, R.sup.7 and R.sup.8 are as described above], can be prepared by reacting compounds represented by the general formula (16) with compounds represented by the general formula (4) ##STR15##
[wherein R, R.sup.1 and R.sup.2 are as described above]. ##STR16##
[wherein X, R.sup.4, R.sup.7 and R.sup.8 are as described above].
It is preferable to conduct the reaction at 0.degree. C. to solvent-refluxing temperature, though the reaction temperature is not restricted particularly, in the presence of inorganic base such as potassium carbonate, potassium t-butoxide or potassium hydride, preferably sodium hydride, using tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, preferably dimethylformamide as a reaction solvent.
In the synthetic route 2, compounds represented by a general formula (6a) ##STR17##
[wherein R.sup.1, R.sup.2, R.sup.4 and R.sup.8 are as described above], can be prepared by hydrolyzing and decarboxylating the compounds represented by the general formula (17) aforementioned.
In the case of acid catalyst, it is preferable to conduct the hydrolysis and decarboxylation by heating to 80 to 120.degree. C., using hydrochloric acid or hydrobromic acid. Moreover, in the case of alkali catalyst, it is preferable to conduct at room temperature in an alcoholic solvent such as methanol or ethanol or in a solvent such as tetrahydrofuran or dimethylformamide, using aqueous solution of sodium hydroxide or aqueous solution of potassium hydroxide.
In the synthetic route 3, compounds represented by a general formula (9) ##STR18##
[wherein R.sup.1, R.sup.2 and R.sup.6 are as described above, R.sup.11 denotes a lower alkyl group with carbon atoms of 1 to 3, and (n, m) denotes a combination of integers of (1, 3) or (2, 2)], can be prepared by reacting compounds represented by a general formula (7) with compounds represented by a general formula (8). ##STR19##
[wherein X, R.sup.1, R.sup.2 and r.sup.6 are as described above]. EQU CH.sub.n (CO.sub.2 R.sup.11).sub.m (8)
[wherein combination of (n, m) and R.sup.11 are as described above].
It is preferable to conduct the reaction at 0.degree. C. to solvent-refluxing temperature, though the reaction temperature is not restricted particularly, in the presence of inorganic base such as potassium carbonate, potassium t-butoxide or potassium hydride, preferably sodium hydride, using tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, preferably dimethylformamide as a reaction solvent.
In the synthetic route 3, compounds represented by a general formula (6b) ##STR20##
[wherein R.sup.1, R.sup.2 and R.sup.6 are as described above], can be prepared by hydrolyzing and decarboxylating the compounds represented by the general formula (9) aforementioned.
In the case of acid catalyst, it is preferable to conduct the hydrolysis and decarboxylation by heating to 80to 120.degree. C., using hydrochloric acid or hydrobromic acid. Moreover, in the case of alkali catalyst, it is preferable to conduct at room temperature in an alcoholic solvent such as methanol or ethanol or in a solvent such as tetrahydrofuran or dimethylformamide, using aqueous solution of sodium hydroxide or aqueous solution of potassium hydroxide.